The present invention relates to novel compounds and methods for the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of certain 15-ketal analogs of F series prostaglandins to treat glaucoma and ocular hypertension.
Glaucoma is a progressive disease which leads to optic nerve damage and, ultimately, total loss of vision. The causes of this disease have been the subject of extensive studies for many years, but are still not fully understood. The principal symptom of and/or risk factor for the disease is elevated intraocular pressure or ocular hypertension due to excess aqueous humor in the anterior chamber of the eye.
The causes of aqueous humor accumulation in the anterior chamber are not fully understood. It is known that elevated intraocular pressure (xe2x80x9cIOPxe2x80x9d) can be at least partially controlled by administering drugs which either reduce the production of aqueous humor within the eye, such as beta-blockers and carbonic anhydrase inhibitors, or increase the outflow of aqueous humor from the eye, such as miotics and sympathomimetics.
Most types of drugs conventionally used to treat glaucoma have potentially serious side effects. Miotics such as pilocarpine can cause blurring of vision and other visual side effects, which may lead either to decreased patient compliance or to termination of therapy. Systemically administered carbonic anhydrase inhibitors can also cause serious side effects, such as nausea, dyspepsia, fatigue, and metabolic acidosis, which side effects can affect patient compliance and/or necessitate the termination of treatment. Moreover, some beta-blockers have increasingly become associated with serious pulmonary side effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics, on the other hand, may cause tachycardia, arrhythmia and hypertension. Recently, certain prostaglandins and prostaglandin derivatives have been described in the art as being useful in reducing intraocular pressure. Typically, however, prostaglandin therapy for the treatment of elevated intraocular pressure is attended by undesirable side-effects, such as irritation and hyperemia of varying severity and duration. There is therefore a continuing need for therapies which control the elevated intraocular pressure associated with glaucoma.
Prostaglandins are metabolite derivatives of arachidonic acid. Arachidonic acid in the body is converted to prostaglandin G2, which is subsequently converted to prostaglandin H2. Other naturally occurring prostaglandins are derivatives of prostaglandin H2. A number of different types of prostaglandins are known in the art including A, B, C, D, E, F, G, I and J-Series prostaglandins (EP 0 561 073 A1). Of interest in the present invention are compounds which are believed to exhibit similar IOP lowering mechanisms to those exhibited by PGF2xcex1, an F-series prostaglandin of the following formula: 
The relationship of PGF2xcex1, receptor activation and IOP lowering effects is not well understood. It is believed that PGF2xcex1 receptor activation leads to increased outflow of aqueous humor. Regardless of mechanism, PGF2xcex1 and certain of its analogs have been shown to lower IOP (Giuffre, The Effects of Prostaglandin F2xcex1the Human Eye, Graefe""s Archive Ophthalmology, volume 222, pages 139-141 (1985); and Kerstetter et al., Prostaglandin F2xcex1-1-Isopropylester Lowers Intraocular Pressure Without Decreasing Aqueous Humor Flow, American Journal of Ophthalmology, volume 105, pages 30-34 (1988)). Thus, it has been of interest in the field to develop synthetic PGF2xcex1 analogs with IOP lowering efficacy.
Synthetic PGF2xcex1-type analogs have been pursued in the art (Graefe""s Archive Ophthalmology, volume 229, pages 411-413 (1991)). Though PGF2xcex1-type molecules lower IOP, these types of molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects include an initial increase in IOP, breakdown of the blood aqueous barrier and conjunctival hyperemia (Alm, The Potential of Prostaglandin Derivatives in Glaucoma Therapy, Current Opinion in Ophthalmology, volume 4, No. 11, pages 44-50 (1993)). Based on the foregoing, a need exists for the development of compounds that may activate the PGF2xcex1 receptors, yielding a more efficacious lowering of IOP, while exhibiting fewer or reduced side effects.
An agent which exhibits comparable efficacy, but with reduced side effects when compared to other agents, is said to have an improved therapeutic profile. It is an object of this invention to provide a class of IOP lowering agents with an improved therapeutic profile over PGF2xcex1, and methods of their use. It has unexpectedly been found that the presently claimed 15-ketal analogs of PGF2xcex1 meet this objective. Although etiproston, a 15-ketal prostaglandin and certain analogs thereof are known in the art (U.S. Pat. No. 4,088,775 and Skuballa, et al., xe2x80x9c15-,15-ketals of Natural Prostaglandins and Prostaglandin Analogues Synthesis and Biological Activities,xe2x80x9d J. Med. Chem, 21(5):443 (1978)), they are known primarily for their luteolytic properties. See, e.g. The Merck Index (Eleventh Ed.) p. 608, monograph no. 3827 (1989). Etiproston was also disclosed in U.S. Pat. No. 5,480,900 as one of many prostaglandin analogs which in combination with a clonidine derivative would be useful for treating glaucoma. In addition, U.S. Pat. No. 4,870,104 discloses 11-halo prostaglandins which may have an ethylenedioxymethylene group at the 15 position. The novel compositions and the methods of use claimed in this application, however, are neither disclosed nor suggested in the foregoing art.
The present invention is directed to novel compounds, ophthalmic compositions and methods of their use in treating glaucoma and ocular hypertension. In particular, the present invention provides certain classes of 15-ketal prostaglandins believed to have functional PGF2xcex1 receptor agonist activity, and methods of their use in treating glaucoma and ocular hypertension.
It has unexpectedly been found that the 15 -ketal substituted PGF2xcex1 analogs of the present invention exhibit an improved therapeutic profile in the treatment of glaucoma and ocular hypertension when compared natural prostaglandins and some of their known analogs. The substituted PGF2xcex1 analogs useful in the methods and compositions of the Ad present invention have the following formula I: 
wherein:
R1=CO2R, CONR4R5, CH2OR6, or CH2NR7R8, where:
R=H or cationic salt moiety, or CO2R=pharmaceutically acceptable ester moiety; R4, R5=same or different=H or alkyl; R6=H, acyl, or alkyl; R7, R8=same or different=H, acyl, or alkyl; with the proviso that if one of R7, R8=acyl, then the other=H or alkyl;
n=0 or 2;
R2=H, alkyl, or acyl;
R3=H, halo, or OR9; where R9=H, alkyl, or acyl;
- - - -=single or non-cumulated double bond, with the provisos that if a double bond is present between carbons 4 and 5, it is of the cis configuration; and that if a double bond is present between carbons 13 and 14, it is of the trans configuration;
X=(CH2)m or (CH2)mO, where m=1-6; and
Y=phenyl, optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, or hydroxy; or
Xxe2x80x94Y=(CH2)pY1; where p=0-6; and 
wherein:
W=CH2, O, S(O)q, NR10, CH2CH2, CHxe2x95x90CH, CH2O, CH2S(O)q, CHxe2x95x90N, or CH2NR9,
where q=0-2, and R10=H, alkyl, or acyl;
Z=H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or hydroxy; and
- - - -=single or double bond.
For purposes of the foregoing and following definitions, the term xe2x80x9cpharmaceutically acceptable esterxe2x80x9d means any ester that would, in appropriate doses, be suitable for therapeutic administration to a patient by conventional means without significant deleterious health consequences; and xe2x80x9cophthalmically acceptable esterxe2x80x9d means any pharmaceutically acceptable ester that would be suitable for ophthalmic application, i.e. non-toxic and non-irritating. Preferred are alkyl esters. Most preferred are C2-C4 alkyl esters, and especially isopropyl esters. In addition, references to xe2x80x9ccarbons 4 and 5xe2x80x9d, xe2x80x9ccarbons 5 and 6xe2x80x9d and xe2x80x9ccarbons 13 and 14xe2x80x9d shall mean the carbons so designated in the structural formulas even when n=2.
Preferred for use in the methods and compositions of the present invention are those compounds of formula I above, wherein:
R1=CO2R, where R=H; or CO2R=ophthalmically acceptable ester moiety;
n=0;
R2=H;
R3=OH in the alpha (xcex1) configuration, or Cl or F in the beta (xcex2) configuration;
xe2x80x94 xe2x80x94 xe2x80x94 =single or non-cumulated double bond, with the provisos that if double bond is present between carbons 4 and 5 or carbons 5 and 6, it is of the cis configuration; and that if a double bond is present between carbons 13 and 14, it is of the trans configuration;
X=CH2O; and
Y=phenyl, optionally substituted with halo or trihalomethyl.
Especially preferred for use in the present invention are the following compounds:
Included within the scope of the present invention are the individual enantiomers of the title compounds, as well as their racemic and non-racemic mixtures. The individual enantiomers can be enantioselectively synthesized from the appropriate enantiomerically pure or enriched starting material by means such as those described below. Alternatively, they may be enantioselectively synthesized from racemic/non-racemic or achiral starting materials. (Asymmetric Synthesis by J. D. Morrison and J. W. Scott, Eds., Academic Press Publishers: New York, 1983-1985 (five volumes) and Principles of Asymmetric Synthesis by R. E. Gawley and J. Aube, Eds., Elsevier Publishers: Amsterdam, 1996). They may also be isolated from racemic and non-racemic mixtures by a number of known methods, e.g. by purification of a sample by chiral HPLC (A Practical Guide to Chiral Separations by HPLC, G. Subramanian, Ed., VCH Publishers: New York, 1994; Chiral Separations by HPLC, A. M. Krstulovic, Ed., Ellis Horwood Ltd. Publishers, 1989), or by enantioselective hydrolysis of a carboxylic acid ester sample by an enzyme (Ohno, M.; Otsuka, M. Organic Reactions, volume 37, page 1 (1989)). Those skilled in the art will appreciate that racemic and non-racemic mixtures may be obtained by several means, including without limitation, nonenantioselective synthesis, partial resolution or even mixing samples having different enantiomeric ratios.
The compounds of the present invention believed to be novel are the cis xcex944 compounds, i.e. those compounds of formula I, wherein:
R1=CO2R, CONR4R5, CH2OR6, or CH2NR7R8; where:
R=H or cationic salt moiety, or CO2R=pharmaceutically acceptable ester moiety; R4, R5=same or different=H or alkyl; R6=H, acyl, or alkyl; R7, R8=same or different=H, acyl, or alkyl; with the proviso that if one of R7, R8=acyl, then the other=H or alkyl;
n=0 or2;
R2=H, alkyl, or acyl;
R3=H, halo, or OR9; where R9=H, alkyl, or acyl;
- - - -=single or non-cumulated double bond, with the provisos that a cis double bond is present between carbons 4 and 5; and that if a double bond is present between carbons 13 and 14, it is of the trans configuration;
X=(CH2)m or (CH2)mO, where m=1-6; and
Y=phenyl, optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, or hydroxy; or
Xxe2x80x94Y=(CH2)pY1; where p=0-6; and 
wherein:
W=CH2, O, S(O)q, NR10, CH2CH2, CHxe2x95x90CH, CH2O, CH2S(O)q, CHxe2x95x90N, or CH2NR9,
where q=0-2, and R10=H, alkyl, or acyl;
Z=H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or hydroxy; and
- - - -=single or double bond.
Preferred novel compounds are those of formula I, wherein:
R1=CO2R; where R=H; or CO2R=pharmaceutically acceptable ester moiety;
n=0;
R2=H;
R3=OH in the alpha (xcex1) configuration, or Cl or F in the beta (xcex2) configuration;
- - - -=single or non-cumulated double bond, with the provisos that a cis double bond is present between carbons 4 and 5 and that if a double bond is present between carbons 13 and 14, it is of the trans configuration;
X=CH2O; and
Y=phenyl, optionally substituted with halo, or trihalomethyl.
Other related PGFs within the scope of the present invention are known and their syntheses are either described in the literature or can be achieved by methods similar to those described in the literature or otherwise known to those of skill in the art (eg. Skuballa et. al. U.S. Pat. No. 4,088,775; Vorbruggen et. al. U.S. Pat. No. 4,870,104). The foregoing references are by this reference incorporated herein.
In the foregoing illustrations, as well as those provided hereinafter, wavy line attachments indicate either the alpha (xcex1) or beta (xcex2) configuration. The carbon numbering is as indicated in structural formula I, even when n=2. A hatched line, as used e.g. at carbon 9, indicates the xcex1 configuration. A solid triangular line indicates the xcex2 configuration. Dashed lines on bonds, e.g. between carbons 5 and 6, indicate a single or double bond. Two solid lines between carbons indicate a double bond of the specified configuration.
In the following Examples 1-6, the following standard abbreviations are used: g=grams (mg=milligrams); mol=moles (mmol=millimoles); mL=milliliters; mm Hg=millimeters of mercury; mp=melting point; bp=boiling point; h=hours; and min=minutes. In addition, xe2x80x9cNMRxe2x80x9d refers to nuclear magnetic resonance spectroscopy and xe2x80x9cMSxe2x80x9d refers to mass spectrometry.